As a consequence of their importance in biomedically useful compounds (anthracycline antibiotics, antineoplastic agents, etc.), highly functionalized aromatic compounds represent a synthetic challenge that has received considerable attention in recent years. The reaction of polyhaloarenes with organometallic reagents, which proceeds via tandem or multiple aryne steps, represents one relatively unexplored solution to this problem. These reactions can be used to construct, in a single operation, from one to six new carbon-carbon bonds in place of the halogens, often with functional differentiation of the appended carbon atoms. Work initiated during the previous grant period focused mainly on aryl Grignard reagents as the organometallics and on a limited number of polyhaloarenes. During the next grant period, these studies will be broadly extended to reactions with much greater potential for application to health-related natural products. Specifically, the methodology will be extended to (1) acyclic and cyclic vinyl, acetylenic, alkyl and heterocyclic organometallics, especially those that possess other latent functionality, (2) to polyhaloarenes which broaden the range of possible substitution patterns and arene nuclei, (3) to organometallics with diene moieties suitably placed for multiple ring constructions via tandem nucleophilic--cycloaddition trapping of successive aryne intermediates, (4) to organometallics other than Grignard reagents and particularly to functionalized lithium reagents, (5) to fundamental studies on the first step in these reactions, i.e., metal-halogen exchange, (6) to other methods of initiating tandem aryne reactions, and (7) to a preliminary study of anion-assisted Diels-Alder reactions.
